The permeability, P(S), to sodium fluorescein (Stokes-Einstein radius = 0.45 nm) has been measured in single mesenteric capillaries of pithed frogs and anaesthetised rats as perfusion velocity, U, was varied over a range from 400 up to 2000-10,000 microm s(-1). P(S) increased linearly with U. In 20 frog capillaries, mean (+/- S.E.M.) P(S) (in microm s(-1)) = 9.35 (+/- 1.55)U x 10(-5) + 0.244 (+/- 0.0291). Similarly, in nine rat venules, mean P(S) = 1.62 (+/- 0.385)U x 10(-4) + 0.375 (+/- 0.025). The flow-dependent component of permeability could be reversibly abolished in frog capillaries by superfusing with 100 microM noradrenaline and by superfusing rat venules with the nitric oxide synthase inhibitor, N(G)-nitro-L-arginine (20 microM). It was shown that changes in microvascular pressure accompanying changes in U during free perfusion could account for only 15 % of the changes in P(S), i.e. 85 % of the changes in P(S) were changes in the permeability coefficient itself. A comparison between the changes in P(S) with U and the previously described changes in microvascular permeability to K(+) with U, suggest that if the flow-dependent component of permeability is modelled as a population of pores of constant size, these have radii of 0.8 nm. Such a pathway would limit flow-dependent permeability to small hydrophilic molecules and have minimal effect on net fluid exchange.